Failure of GPI compounds to display neurotrophic activity in vitro and in vivo

The effects of cold preservation and subimmunosuppressive doses of FK506 on axonal regeneration in murine peripheral nerve isografts

“…The neuroregenerative effects of FK506 are now thought to be independent of calcineurin, but to still involve binding to FKBP-12, or perhaps another binding ligand such as FKBP-52 (19)(20)(21)59). The administration of other nonimmunosuppressive FKBP-12-binding ligands has demonstrated a neuroregenerative effect in some in vivo (25,26,60,61) and in vitro studies (21,22,62), but not in others (23,24,63,64). By demonstrating a neuroregenerative effect in the absence of immunosuppression, the present study provides further in vivo evidence that the neuroregenerative and immunosuppressive effects of FK506 are distinct from one another.…”

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

“…Reduction of the C2,C3 olefin in WYE-592 via catalytic hydrogenation to yield ILS-920 precluded the possibility of such a retro Diels-Alder reaction in the product, and the compound was observed to have no effect on T cell proliferation up to 5 M. Moreover, ILS-920 was almost five times more potent than WYE-592 at promoting cortical neuronal survival (and therefore an order of magnitude more potent than rapamycin). Both compounds demonstrated greater activity in these neuronal assays than the previously reported nonimmunosuppressive immunophilin ligand GPI-1046 (22)(23)(24).…”

“…GPI1046 has been reported to stimulate neurite outgrowth in chicken sensory ganglia at picomolar concentrations and to stimulate recovery after sciatic nerve crush (22). However, other reports represent the neuroprotective activity of GPI1046 as being marginal in neurite outgrowth studies in chicken DRG explants, rat DRGs, and a sciatic nerve injury model (23,24). In view of these discrepancies, it was proposed that neuroprotection is mediated by immunophilins other than FKBP12, notably FKBP52 and FKBP38 (5, 6).…”

“…The in vivo efficacy of ILS-920 is in marked contrast to rapamycin, which failed to reduce infarct volume in a rat tMCAO model (16). GPI-1046 also was reported to have limited or no efficacy in comparable models of ischemic stroke (24). N-(NЈ,NЈ-dimethylcarboxamidomethyl)cycloheximide (DM-CHX) was reported to reduce infarct volume by up to 44% when delivered via intracerebroventricular (i.c.v.)…”

Neurodegeneration and neuroprotection in Parkinson disease

“…140,141 On the other hand, there have been many reports that failed to find such benefits in various animal models of PD, including primates. [142][143][144][145] One controlled clinical trial testing neuroimmunophilin in patients was unsuccessful, but a larger one is now underway.…”